Treating the devastating loss of memory associated with aging or neurodegenerative disease requires that we first understand the basic cellular mechanisms of memory. Small conductance calcium-activated potassium (SK) channels play a fundamental role in shaping the responses of neurons in brain regions known to be critical for memory. SK channels are also functionally coupled to a well recognized cellular mechanism of memory, the NMDA-type glutamate receptor. NMDA receptor activity is considered by many to be essential for synaptic changes that underlie memory formation. Activation of SK channels reduces excitatory NMDA receptor responses and shunts NMDA receptor-dependent synaptic plasticity. Therefore, SK channels are in a unique position to influence memory processes. The goals of this application are to understand: A) the distinct influence of SK channels in the hippocampus and in the lateral amygdala on the processes of memory encoding, retention, retrieval and extinction; B) the consequence of specific blockade of SK2 channels, or the specific activation of SK3 and SK2 channels on hippocampal and amygdala memory processes; C) the efficacy of SK channel blockers to rescue the memory deficits found in mice that overexpress SK2 channels; and D) the potential for dendritic SK2 channels in the lateral amygdala to be internalized after the encoding of new fear memories. These experiments combine Pavlovian fear conditioning paradigms with region-specific intracranial microinfusions to define the influence of brain SK channels on memory processes. The final aim involves a collaborative effort with Dr. John Adelman (Co- Investigator) to conduct ultrastructural analyses of synapses of lateral amygdala neurons after fear conditioning. Our preliminary findings indicate that the SK channel blocker, apamin enhances memory, while the SK channel activator, 1-EBIO impairs memory. Evidence also suggests that memory encoding or the formation of new memory is uniquely sensitive to SK channel blockers and activators. The lack of effect of SK channel drugs on later stages of memory suggests that SK channels may undergo a form of plasticity during learning - perhaps removal from the dendritic spine surface. Together, the proposed studies will provide insights into the relatively underdeveloped field of memory modulation. The studies will improve knowledge of the mechanisms involved in distinct memory processes, including extinction of memory. These studies will also contribute to defining targets for novel therapies to combat impairments of memory that result from aging and neurological disorders, a well as treatments for fear and anxiety disorders. PUBLIC HEALTH RELEVANCE: The proposed studies will provide insights into the fundamental basic biology of memory. The project will highlight mechanisms of several memory processes and aid the development of novel therapies to combat impairments of memory that result from aging, neurodegenerative disorders, and fear or anxiety disorders.